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1 Corticosteroids
Scammell
87
Pharmacology
Graduate
04/17/2010

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Cards

Term
what type of secretion does cortisol undergo?
Definition
diurnal variation
Term
when are levels of cortisol highest?
Definition
at about 8 am in the morning
Term
what stimulates cortisol secretion?
Definition
stimulated by ACTH on the adrenal gland
Term
what is the hypothalamic hormone that stimulates release of cortisol?
Definition
CRH
Term
what is the effect of CRH on the pituitary?
Definition
stimulate ACTH release from corticotrophs in the anterior pituitary
Term
what is the effect of ACTH on the adrenal gland?
Definition
stimulate receptors in the zona fasciculata stimulates cortisol synthesis and secretion
Term
how is cortisol negatively controlled?
Definition
negative feedback by circulating cortisol
Term
what is necessary in the regulation of circulating cortisol?
Definition
negative feedback shuts off endogenous production of corticosteroids
Term
steroid hormone biosynthesis as a whole uses a variety of different what?
Definition
cytochrome p450s
Term
why is it important that adrenocortical hormone biosynthesis is dependent on many different cytochrome p450s?
Definition
because they can be regulated and affected by a number of different agents
Term
what is the precursor of steroid hormones?
Definition
cholesterol
Term
what is the main site of regulation of steroid hormone synthesis?
Definition
first enzyme - 20,22-desmolase or cholesterol side chain cleavage

converts cholesterol
Term
what determines what hormone is made from cholesterol precursor?
Definition
which enzymes are present
Term
cytochrome p450 systems use what 2 things for their reactions?
Definition
molecular oxygen and NADPH
Term
what is the importance of knowing that steroid hormone synthesis is dependent on cytochrome p450 systems?
Definition
they are inducible and inhibitable by other drugs
Term
steroid hormone state in plasma?
Definition
avidly bound in circulation by binding globulins
Term
can steroid hormones cross the plasma membrane?
Definition
YES

they are highly lipophilic
Term
what is true about a steroid hormone that can enter a cell and bind to its receptor?
Definition
it has to be in free form (not bound to plasma binding globulin)
Term
what are the 3 components of steroid receptors?
Definition
1. N terminal region - transcriptional activation domain
2. DNA binding region - central region that binds the receptor to the response element on DNA
3. ligand binding region - where hormone binds
Term
what is the state of steroid receptors in the cytoplasm or nucleus before they are bound by their hormone?
Definition
they are associated with chaperones
Term
what is the function of chaperones associated with steroid hormone receptors?
Definition
they maintain the receptor in a high affinity state
Term
what are the 3 chaperones for cortisol receptor?
Definition
1. HSP70
2. HSP90
3. IP - immunophilin
Term
how do steroid receptors elicit a response in the cell?
Definition
they act as transcription factors activating genes through specific response elements
Term
what binds cortisol in the blood?
Definition
corticosteroid binding globulin (CBG) or transportin
Term
all steroid hormones have what underlying structure?
Definition
4 rings - A to D
Term
what is the structure of cortisol?
Definition
its a C-21 steroid with 4 rings
Term
how is cortisol metabolized?
Definition
by successive reduction in the A ring

reduced in 3 steps
Term
what is the purpose of cortisol metabolism?
Definition
it makes a more water soluble metabolite that can be excreted in the urine

happens with all steroids
Term
what are the 3 MAJOR metabolic effects of adrenal steroids?
Definition
1. CHO, protein, and fat metabolism - increase gluconeogenesis
2. electrolyte and water metabolism
3. anti-inflammatory and immunosuppressive effects
Term
what happens to plasma glucose levels with adrenal steroids administration?
Definition
increase

can cause hyperglycemia
Term
what happens to amino acids with adrenal steroids administration?
Definition
they are mobilized from tissues
Term
what happens to glucose uptake with adrenal steroids administration?
Definition
it is inhibited in fat cells
Term
what can be an effect of long term use of adrenal steroids on muscle?
Definition
can lead to breakdown of muscle and muscle wasting
Term
how do adrenal steroids affect electrolyte and water metabolism?
Definition
1. increases Na reabsorption
2. increases K secretion/excretion
3. inhibits Ca absorption from intestine
Term
how do adrenal steroids inhibit Ca absorption from the intestine?
Definition
act as an antagonist of vitamin D activity in the gut - vitamin D is normally involved in Ca absorption

leads to an increase Ca loss in feces
Term
what 3 ways do adrenal steroids act as anti-inflammatory and immunosuppressive agents?
Definition
1. inhibition of arachidonic acid and its metabolites
2. inhibit cytokine production and release
3. inhibit production of adhesion molecules
Term
what 2 enzymes in the arachidonic acid pathway do adrenal steroids inhibit?
Definition
COX2 and phospholipase A2
Term
what is the function of COX 2 in the arachidonic acid pathway?
Definition
normally converts AA to PGE

inhibited by adrenal steroids
Term
what is the function of phospholipase A2 in the arachidonic acid pathway?
Definition
normally responsible for synthesis of AA

inhibited by adrenal steroids
Term
how do adrenal steroids inhibit cytokine production and release?
Definition
block NF Kappa B which is needed for interleukins
Term
what adhesion molecules are inhibited by adrenal steroids?
Definition
ELAM1 and ICAM1
Term
where does inhibition of adhesion molecules with adrenal steroids occur?
Definition
in endothelial cells
Term
what effects of adrenal steroids are seen at physiological concentrations of corticosteroids?
Definition
1. carbohydrate, protein, and fat metabolism
2. electrolyte and water metabolism
Term
when are the anti-inflammatory and immunosuppressive effects of adrenal steroids seen?
Definition
only at higher than physiological concentrations of corticosteroids
Term
how are adrenal steroids involved in the response to tissue injury?
Definition
inhibit the response to injury by blocking the mediators of the response
Term
what are some clinical uses of synthetic glucocorticoids?
Definition
allergic reactions
collagen-vascular disorders
eye diseases
GI disease
heme disorders
infections
inflammatory conditions of bones and joints
neurologic disorders
organ transplants
pulmonary disease
renal disorders
skin diseases
thyroid disease
hypercalcemia
mountain sickness
Term
forms of glucocorticoid administration?
Definition
many different ways - injected into joints, inhalants, topically, orally
Term
what is the the only thing synthetic glucocorticoids are used to treat?

why is it used in so many other disorders?
Definition
adrenal insufficiency

it is used to alleviate the symptoms of other disorder
Term
what are the 2 goals of synthetic products of cortisol?
Definition
1. reduce the salt retaining activity
2. make a longer acting and more potent glucocorticoid
Term
what are the 3 main categories of glucocorticoids?
Definition
1. short acting
2. intermediate acting
3. long acting
Term
2 short acting glucocorticoids?
Definition
1. hydrocortisone
2. prednisone
Term
how does hydrocortisone compare to endogenous cortisol?
Definition
has the same activity
Term
how does prednisone compare to endogenous cortisol?
Definition
4x anti-inflammatory action
1/3 salt retaining activity - avoid HTN

still short acting
Term
what is the intermediate acting glucocorticoid?
Definition
triamcinosone
Term
how does triamcinosone compare to endogenous cortisol?
Definition
higher anti-inflammatory (5x)
NO salt retaining activity
Term
what are the long acting glucocorticoids?
Definition
1. dexamethasone
2. betamethasone
Term
how does dexamethasone compare to endogenous cortisol?
Definition
very potent anti-inflammatory action (30x)
NO salt retaining activity
Term
what mineralocorticoid is used as a drug?
Definition
fludrocortisone
Term
how does fludrocortisone compare to endogenous cortisol?
Definition
has some anti-inflammatory activity
salt retaining activity is 250x higher
Term
activity of beclomethasone?
Definition
long to intermediate acting
Term
salt retaining activity of beclomethasone?
Definition
very low
Term
use of beclomethasone?
Definition
for treatment of asthma in inhalant preparations
Term
are synthetic corticosteroids orally active?
Definition
YES

all steroids are orally active
peptide hormones are not
Term
what has to happen to cortisone, prednisone, and methylprednisone before they are effective in the body?
Definition
they have to be activated in the body
Term
what enzyme is responsible for activation of cortisone, prednisone, and methylprednisone?
Definition
hepatic 11 beta-hydroxysteroid dehydrogenase 1
Term
what does hepatic 11 beta-hydroxysteroid dehydrogenase do?
Definition
activates:
methylprednisone to methylprednisolone
prednisone to prednisolone
cortisone to cortisol
Term
activation of cortisone, prednisone, and methylprednisone by hepatic 11 beta-hydroxysteroid dehydrogenase 1 normally occurs how?
Definition
very rapidly upon oral administration
Term
side effects of corticosteroid therapy (6 main types)?
Definition
1. endocrine-metabolic
2. cardiovascular
3. musculoskeletal
4. nervous disorders - mood disorders
5. increase infections
6. cataracts in children
Term
what are the endocrine side effects of corticosteroid therapy?
Definition
1. hyperglycemia - stimulates gluconeogenesis
2. retarded somatic growth - in children
3. negative N and Ca balance
4. retain Na and water - stimulates aldosterone
5. suppression HPA - significantly endogenous cortisol production
Term
why do you have taper down drug dosage of coricosteroids rather than remove them immediately after use?
Definition
to allow endogenous mechanisms to recover from the suppression of the HPA axis and endogenous cortisol secretion that can occur
Term
what are the cardiovascular side effects of corticosteroid therapy?
Definition
HTN from Na reabsorption
Term
what are the musculoskeletal side effects of corticosteroid therapy?
Definition
myopathy - muscle wasting from amino acid mobilization and conversion to glucose

anti-vitamin D effects can lead to long term Ca loss from bones and osteoporosis
Term
what happens to host defenses as a side effect of corticosteroid therapy?
Definition
they are decreased and lead to an increased susceptibility to opportunistic infections
Term
what is an important side effect of corticosteroid therapy in children and why?
Definition
can cause cataracts with parenteral use that are irreversible
Term
use of topical glucocorticoids?
Definition
for resp, dermatologic (psoriasis, poison ivy) and many other uses
Term
2 topical glucocorticoids?
Definition
1. budesonide
2. flunisolide

used in metered dose inhalers for asthma
Term
is budesonide absorbed orally?
Definition
relatively poorly absorbed orally
Term
use of budesonide?
Definition
inflammatory bowel disease
Term
side effects of inhaled steroids?
Definition
oral candidiasis and dysphonia due to local deposition in the mouth and throat
Term
mechanism of action of aminoglutethimide and ketoconazole?
Definition
inhibit cortisol (steroid hormone) biosynthesis and decrease cortisol secretion
Term
aminoglutethimide and ketoconazole use?
Definition
in patients with Cushing's

inhibit cortisol biosynthesis and decrease cortisol secretion
Term
what 2 drugs can be used to inhibit cortisol biosynthesis and decrease cortisol secretion in patients with Cushing’s?
Definition
aminoglutethimide and ketoconazole
Term
what drug can be used in inoperable adrenocortical carcinoma?
Definition
mitotane
Term
mechanism of action of mitotane?
Definition
causes selective destruction of adrenocortical cells
Term
The poorly absorbed synthetic glucocorticoid budesonide taken orally is used to treat inflammatory bowel disease. This reduces the incidence of side effects of long-term therapy with better absorbed corticosteroids such as prednisone. Systemic side effects of oral prednisone include:

a. Hypoglycemia
b. Hypercalcemia
c. Postural hypotension
d. Changes in mood
Definition
d. Changes in mood
Term
can topically applied corticosteroids lead to systemic side effects?
Definition
YES

if applied to certain areas of the body with high circulation or absoprtion
Term
what is the best place for absorption of corticosteroids in a man?
Definition
scrotum
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